Note: Intro -- Preface -- Contents -- Contributors -- Chapter 1: Small RNA-Guided Transcriptional Gene Activation (RNAa) in Mammalian Cells -- 1.1 Introduction -- 1.2 A Historical View of RNAa -- 1.3 Basic Characteristics of RNAa -- 1.3.1 Indispensable Role of Ago in RNAa -- 1.3.2 Effective Concentrations of saRNA in RNAa -- 1.3.3 Kinetics of RNAa -- 1.3.4 Activation of Endogenous Promoters Leads to Relevant and Predictable Functional Consequences -- 1.4 Design Rules for Exogenous RNAa -- 1.5 Targeting Rules for Endogenous RNAa -- 1.6 RNAa Is Distinct from Nuclear RNAi -- 1.7 Is DNA or RNA the Target? -- 1.8 RNAa Occurs at the Transcriptional Level and Acts on Transcription Initiation and Elongation -- 1.9 The RNA-Induced Transcriptional Activation (RITA) Complex -- 1.10 A Working Model for RNAa -- 1.11 Potential Applications of RNAa -- 1.11.1 Interrogating Gene Function -- 1.11.2 Cell Fate Reprogramming -- 1.11.3 Preclinical Study of RNAa Therapeutics -- 1.12 Concluding Remarks -- References -- Part I: Exogenous RNAa -- Chapter 2: Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation -- 2.1 Introduction -- 2.2 RNAa Stimulation of Emx2 -- 2.3 saRNAs as General Tools for Therapy of Neuropathogenic Haploinsufficiencies? -- 2.4 Selecting miRNA-Like saRNAs Upregulating Foxg1-mRNA -- 2.5 Compliance of Foxg1-RNAa with Endogenous Tuning of Foxg1-mRNA -- 2.6 Molecular Mechanisms Underlying Foxg1-RNAa -- 2.7 In Vivo Foxg1-RNAa -- 2.8 Concluding Remarks -- References -- Chapter 3: Target-Recognition Mechanism and Specificity of RNA Activation -- 3.1 Introduction -- 3.2 Target-Recognition Mechanism of RNAi -- 3.3 Discovery of RNAa -- 3.4 Target-Recognition Mechanism of RNAa -- 3.4.1 Distribution of Target Sequence in Gene Promoter. , 3.4.2 A ``Seed Region´´ in Antisense Strand of the saRNA Is Pivotal for Target Recognition -- 3.4.3 Interaction Between saRNA and Promoter DNA -- 3.4.3.1 Antisense Transcripts Mediated RNAa -- 3.4.3.2 RNA Activation Is an ``On-Site´´ Process in Promoter DNA -- 3.4.3.3 saRNA Binds to Promoter DNA -- 3.4.4 Complexity of Target-Recognition Mechanism for RNA Activation -- 3.5 Specificity of saRNA -- 3.6 Conclusions -- References -- Chapter 4: Promoter-Targeted Small Activating RNAs Alter Nucleosome Positioning -- 4.1 Introduction -- 4.2 Nucleosome Repositioning Induces an Open Chromatin Structure in RNAa -- 4.3 RNAPII Is Recruited to the Open Chromatin Structure in RNAa -- 4.4 Potential Role of Cis-Acting Elements in RNAa -- 4.5 Mechanism of Small RNA Activation -- References -- Part II: Endogenous RNAa -- Chapter 5: Endogenous miRNAa: miRNA-Mediated Gene Upregulation -- 5.1 Introduction -- 5.2 Promoter-Targeting miRNAs -- 5.2.1 miR-373 -- 5.2.2 miR-744 -- 5.2.3 miR-589 -- 5.2.4 miR-324-3p -- 5.2.5 miR-551b-3p -- 5.2.6 miR-1236 and miR-6734 -- 5.2.7 TATA-Box-Binding miRNAs -- 5.3 Enhancer-Activating miRNAs -- 5.4 Concluding Remarks and Perspectives -- References -- Chapter 6: miRNA-Mediated RNA Activation in Mammalian Cells -- 6.1 Introduction -- 6.2 History -- 6.3 Maturation of miRNAs -- 6.3.1 Transport of Mature miRNA to the Nucleus for RNAa -- 6.4 Target Specificity and Selection for miRNA-Mediated RNAa -- 6.4.1 Mechanism of Transcriptional Activation -- 6.5 Conclusion -- References -- Chapter 7: RNAa Induced by TATA Box-Targeting MicroRNAs -- 7.1 Introduction -- 7.2 Discovery and Overview of RNAa Induced by TATA Box-Targeting miRNAs -- 7.2.1 Discovery of HIV-1-Encoded miRNA, miR-H3, Which Targets HIV-1 TATA Box -- 7.2.2 Systematic Identification of Cellular TATA Box-Targeting miRNAs. , 7.3 Physiological Significance of RNAa Induced by TATA Box-Targeting miRNAs -- 7.3.1 RNAa Induced by TATA Box-Targeting miRNA and HIV-1 Replication -- 7.3.2 RNAa Induced by TATA Box-Targeting miRNA and CD4+ T Cell Death in HIV-1 Infection -- 7.4 Mechanism of RNAa Induced by TATA Box-Targeting miRNAs -- 7.4.1 Current Model of Promoter-Targeting RNAa Mediated by Small RNAs -- 7.4.2 No Evidence of paRNA or Epigenetic Modification Change Is Involved in RNAa Induced by TATA Box-Targeting miRNAs -- 7.4.3 TATA Box-Targeting miRNAs Facilitate Pol II Pre-initiation Complex Assembly and Transcription Initiation -- 7.5 Rational Design of TATA Box-Targeting saRNAs to Activate Gene Expression -- 7.6 Summary -- References -- Chapter 8: miRNA-Mediated RNAa by Targeting Enhancers -- 8.1 Introduction -- 8.2 Localization and Function of miRNAs -- 8.2.1 Localization of miRNAs in the Nucleus -- 8.2.2 Positive Regulation of Gene Expression by miRNAs -- 8.2.3 Tissue-Specific miRNAs -- 8.3 Characteristics of Enhancers -- 8.3.1 Definition of Enhancers -- 8.3.2 Tissue-Specific Enhancers -- 8.4 NamiRNAs-Mediated RNAa by Targeting Enhancers -- 8.4.1 Overlap of miRNAs and Enhancers -- 8.4.2 Enhancer Activation by NamiRNAs -- 8.4.3 Gene Activation by Enhancers -- 8.4.4 Two Faces of miRNAs -- 8.5 Mechanism of miRNA-Mediated RNAa -- 8.5.1 Original Source of NamiRNAs -- 8.5.2 Is It Possible That miRNAs Act as an Enhancer Trigger by Binding to Enhancers? -- 8.5.3 What Is the Function of AGO2 Protein on NamiRNA-Mediated RNAa? -- 8.5.4 Interaction of miRNAs with Enhancers -- 8.6 Prospects and Challenges of NamiRNA Research -- 8.6.1 Biological Significance of NamiRNA-Mediated RNAa -- 8.6.2 The Dual Functions of miRNAs: Activation and Repression -- 8.6.3 Prospects for Future Research -- References -- Part III: RNA Activation Guided by Other Small RNAs. , Chapter 9: Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames -- 9.1 Introduction -- 9.2 Translation Initiation -- 9.3 Many mRNAs Contain Upstream Open Reading Frames That Can Inhibit Translation of the Main Proteins -- 9.4 Antisense Oligonucleotides -- 9.5 Protein Levels Can Be Increased Using ASOs Targeting uORFs Both in vitro and in vivo -- 9.6 The uORF ASOs Are Highly Specific in Increasing the Levels of Proteins -- 9.7 uORF-Targeting ASOs can Increase Protein Levels by Enhancing Translation -- 9.8 The uORF ASOs Require Proper Affinity to the mRNAs to Increase Protein Levels -- 9.9 Additional Notes -- 9.10 Perspectives -- References -- Chapter 10: Repurposing CRISPR System for Transcriptional Activation -- 10.1 Introduction -- 10.2 CRISPRa Activation Systems -- 10.2.1 The dCas9-VP64 CRISPRa System -- 10.2.2 The dCas9-SunTag CRISPRa System -- 10.2.3 The dCas9-VPR CRISPRa System -- 10.2.4 The sgRNA-Activation Domain of CRISPRa System -- 10.2.5 The Combined CRISPRa System -- 10.2.6 The dCas9-Epigenetic Modifier CRISPRa System -- 10.3 Advantages of CRISPRa System -- 10.4 Applications and Limitations of CRISPRa System -- References -- Part IV: Developing RNAa-Based Therapeutics -- Chapter 11: RNA-Mediated Gene Activation: Identifying a Candidate RNA for Preclinical Development -- 11.1 Introduction -- 11.2 Origin of Activating RNA Hypothesis -- 11.3 Mechanism of Gene Activation -- 11.4 Nuclear RNAi -- 11.5 Nuclear RNAi and Drug Discovery -- 11.5.1 Selection of Target Gene -- 11.5.2 Target Validation -- 11.5.3 Dealing with Off-Target Effects -- 11.5.4 Testing a Nuclear RNAi Mechanism -- 11.6 First Steps Beyond Lead Identification -- 11.7 Other Options for Nuclear RNAi -- 11.8 Case Study: Activating Expression of Frataxin -- 11.9 Summary -- References. , Chapter 12: Treatment of Pancreatic Cancer by Aptamer Conjugated C/EBPα-saRNA -- 12.1 Introduction -- 12.2 Small Activating RNAs (saRNAs) -- 12.3 Aptamer Selection for Targeting Modalities -- 12.4 Pancreatic Cancer Specificity of Aptamers -- 12.5 Aptamer-saRNA Conjugates -- 12.6 In Vitro Assay of Aptamer-saRNA Conjugates -- 12.7 In Vivo Assay of Aptamer-saRNA Conjugates -- 12.8 Summary -- References -- Chapter 13: Treatment of Liver Cancer by C/EBPA saRNA -- 13.1 Introduction -- 13.1.1 Liver Cancer -- 13.1.2 CCAAT/Enhancer-Binding Protein Alpha (C/EBPα) -- 13.2 C/EBPα saRNA in the Treatment of HCC -- 13.2.1 C/EBPα saRNA in a Rat HCC Model -- 13.2.2 Preclinical Development of C/EBPα saRNA for Treatment of HCC -- References -- Chapter 14: Enhancing Angiogenesis in Mice by VEGF-Targeting Small Activating RNAs -- 14.1 Introduction -- 14.1.1 Cardiovascular Disease -- 14.1.2 Vascular Endothelial Growth Factors -- 14.2 Inducing Angiogenesis in Mice -- 14.2.1 Small Hairpin RNAs Can Regulate VEGF-A Via Epigenetic Mechanisms -- 14.2.2 Off-Target Effects of shRNAs Mediating Transcriptional Regulation -- 14.2.3 In Vivo Gene Therapy Using VEGF-A-Activating shRNAs -- 14.3 Future Perspectives for Therapeutics -- 14.3.1 Moving to Large Animal Models -- 14.3.2 Future Perspectives -- 14.4 Conclusions -- References -- Chapter 15: Suppression of Prostate Cancer Metastasis by DPYSL3-Targeted saRNA -- 15.1 Metastasis Is a Key Obstacle in Prostate Cancer Management -- 15.2 DPYSL3 (CRMP4) Is a Metastasis Suppressor in Prostate Cancer -- 15.3 Small Activating RNA Enhances DPYSL3 Gene Expression -- 15.4 PSMA Aptamer-Mediated Prostate Cancer-Specific DPYSL3 Gene Expression in Vivo -- 15.5 RhoA Signal Pathway Is Involved in DPYSL3-Mediated Metastasis Suppression -- 15.6 Conclusion -- References -- Chapter 16: Development of Therapeutic dsP21-322 for Cancer Treatment. , 16.1 Introduction.